P1552: AN IMMUNE ATLAS OF THE DYSFUNCTIONAL CELLULAR AND ANTIBODY RESPONSE TO COVID-19 VACCINATION IN HEMATOLOGICAL PATIENTS WITH A MATURE B-CELL NEOPLASM
Authors: Esperanza Martín-Sánchez, Camila Guerrero, Luis-Esteban Tamariz-Amador, Anastasiia Zherniakova, Aintzane Zabaleta, Catarina Maia, Laura Blanco, Maria-Antonia Fortuño, Carlos Grande, Andrea Manubens, Jose-Maria Arguiñano, Clara Gomez Perez, Ernesto Perez Persona, Iñigo Olazabal Eizaguirre, Itziar Oiartzabal, Carlos Panizo, Felipe Prosper, Jesús San Miguel, Paula Rodríguez-Otero, Bruno Paiva
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Patients with a mature B-cell neoplasm are at high risk of severe infections and poor vaccine immunogenicity. The cell-specific extent of immune dysfunction of these patients prior and during vaccination is poorly described. Aims: Characterize the immune response to vaccination in patients with a mature B-cell neoplasm using COVID-19 vaccines as a case study. Methods: This study included 82 patients with a mature B-cell neoplasm (53 and 29 with a B-cell and a plasma cell disorder, respectively) and 96 age-matched health care practitioners (HCP). A total of 1,104 peripheral blood and serum samples were collected before and at days 7 and 14 after the first dose, as well as at days 7 and 62 after the second. Also before and 17 days after a booster (~five months after the second dose). All individuals received mRNA vaccines. Immune profiling was performed using multidimensional and computational flow cytometry that systematically analyzed 56 immune cell-types per sample. Serum levels of IgM, IgG and IgA against four viral antigens (receptor-binding domain –RBD- of the spike glycoprotein, spike glycoprotein, nucleocapsid and main protease) were quantified using a multiplex-microsphere-based flow cytometry assay. SARS-CoV-2-specific CD8 T cells were quantified using a dextramer panel of spike, membrane, ORF3 and nucleocapsid proteins. Results: Using HCP as a reference of immune response to COVID-19 vaccination, we observed significant deviations at baseline and longitudinally in basophils, eosinophils, neutrophils, 2/6 antigen-presenting cell, 8/18 CD4 and 3/12 CD8 T-cell, and 15/17 B-cell subsets. For example, in HCP there was an initial expansion of classical monocytes followed by constriction; in patients there was a significant reduction of these cells at day 14 after the first dose and thereafter. Another example, most subsets of the B-cell compartment were expanded during vaccination in HCP and patients, but the extent of which was significantly reduced in the later. Accordingly, anti-RBD and anti-spike IgM, IgG and IgA indexes over time were significantly lower in patients vs HCP. Based on differences in immune-cell distribution between both groups, we calculated an immune dysregulation longitudinal cumulative score in each individual that included 48,776 immune parameters in total. We found 19 patients with a score different from that of HCP, and 57% of them had reduced anti-RBD IgG levels two months after the second dose. While SARS-CoV-2-specific CD8 T cell percentages after the second dose were similar between patients and HCP, there was a significant enrichment of TEMRA cells in the former. Virus-specific CD8 T cell and antibody levels decreased ~five months after the second dose in both groups. Importantly, the booster significantly increased virus-specific CD8 T cells within the CD8 compartment (0.08 to 0.14%, P=.02) and anti-RBD IgG levels (20,184 to 186,629 IU/mL, P<.001) in HCP, but not in patients (P≥.26). Furthermore, there was a significant increment of SARS-CoV-2-specific CD8 T cells with an effector memory phenotype in HCP after the booster, whereas no differences were observed in the antigen-dependent differentiation of these cells in patients. Summary/Conclusion: This study provides an atlas of the immune dysfunction in patients with a mature B-cell neoplasm and how it affects the efficacy of vaccination strategies such as for COVID-19. The schedule of vaccine doses and boosters may thus benefit from individualization according to patients’ immune status, which could act as a surrogate of host, tumor and treatment-related immune dysfunction. Keywords: COVID-19, Hematological malignancy, Vaccination, Immune response